2025
Cell

Regulation of inflammatory responses by pH-dependent transcriptional condensates

Authors:

Zhongyang Wu, Scott D. Pope, Nasiha S. Ahmed, Diana L. Leung, Yu Hong, Stephanie Hajjar, Cathleen Krabak, Zhe Zhong, Krishnan Raghunathan, Qiuyu Yue, Diya M. Anand, Elizabeth B. Kopp, Daniel Okin, Weiyi Ma, Ivan Zanoni, Jonathan C. Kagan, Jay R. Thiagarajah, Diana C. Hargreaves, Ruslan Medzhitov, Xu Zhou

Keywords:

transcriptional condensates; gene expression; inflammatory response; BRD4; pH; acidosis; histidine; macrophage; innate immunity; IDR

Abstract:

Inflammation is an essential defense response but operates at the cost of normal tissue functions. Whether and how the negative impact of inflammation is monitored remains largely unknown. Acidification of the tissue microenvironment is associated with inflammation. Here, we investigated whether macrophages sense tissue acidification to adjust inflammatory responses. We found that acidic pH restructured the inflammatory response of macrophages in a gene-specific manner. We identified mammalian BRD4 as an intracellular pH sensor. Acidic pH disrupts transcription condensates containing BRD4 and MED1 via histidine-enriched intrinsically disordered regions. Crucially, a decrease in macrophage intracellular pH is necessary and sufficient to regulate transcriptional condensates in vitro and in vivo, acting as negative feedback to regulate the inflammatory response. Collectively, these findings uncovered a pH-dependent switch in transcriptional condensates that enables environment-dependent control of inflammation, with a broader implication for calibrating the magnitude and quality of inflammation by the inflammatory cost.